64Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques: studies in patients undergoing endarterectomy

Sune Folke Pedersen; Benjamin Vikjær Sandholt; Sune Høgild Keller; Adam Espe Hansen; Andreas Ettrup Clemmensen; Henrik Sillesen; Liselotte Højgaard; Rasmus Sejersten Ripa; Andreas Kjær

doi:10.1161/ATVBAHA.114.305067

⁶⁴Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques: studies in patients undergoing endarterectomy

Sune Folke Pedersen, Benjamin Vikjær Sandholt, Sune Høgild Keller, Adam Espe Hansen, Andreas Ettrup Clemmensen, Henrik Sillesen, Liselotte Højgaard, Rasmus Sejersten Ripa, Andreas Kjær

65 Citations (Scopus)

Abstract

Objective-A feature of vulnerable atherosclerotic plaques of the carotid artery is high activity and abundance of lesion macrophages. There is consensus that this is of importance for plaque vulnerability, which may lead to clinical events, such as stroke and transient ischemic attack. We used positron emission tomography (PET) and the novel PET ligand [⁶⁴Cu] [1,4,7,10-tetraazacyclododecane-N,N′,N″,N⌄-tetraacetic acid]-d-Phe1,Tyr3-octreotate (⁶⁴Cu-DOTATATE) to specifically target macrophages via the somatostatin receptor subtype-2 in vivo. Approach and Results-Ten patients underwent simultaneous PET/MRI to measure ⁶⁴Cu-DOTATATE uptake in carotid artery plaques before carotid endarterectomy. ⁶⁴Cu-DOTATATE uptake was significantly higher in symptomatic plaque versus the contralateral carotid artery (P<0.001). Subsequently, a total of 62 plaque segments were assessed for gene expression of selected markers of plaque vulnerability using real-time quantitative polymerase chain reaction. These results were compared with in vivo ⁶⁴Cu-DOTATATE uptake calculated as the mean standardized uptake value. Univariate analysis of real-time quantitative polymerase chain reaction and PET showed that cluster of differentiation 163 (CD163) and CD68 gene expression correlated significantly but weakly with mean standardized uptake value in scans performed 85 minutes post injection (P<0.001 and P=0.015, respectively). Subsequent multivariate analysis showed that CD163 correlated independently with ⁶⁴Cu-DOTATATE uptake (P=0.031) whereas CD68 did not contribute significantly to the final model. Conclusions-The novel PET tracer ⁶⁴Cu-DOTATATE accumulates in atherosclerotic plaques of the carotid artery. CD163 gene expression correlated independently with ⁶⁴Cu-DOTATATE uptake measured by real-time quantitative polymerase chain reaction in the final multivariate model, indicating that ⁶⁴Cu-DOTATATE PET is detecting alternatively activated macrophages. This association could potentially improve noninvasive identification and characterization of vulnerable plaques.

Original language	English
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
Volume	35
Issue number	7
Pages (from-to)	1696-1703
Number of pages	8
ISSN	1079-5642
DOIs	https://doi.org/10.1161/ATVBAHA.114.305067
Publication status	Published - 27 Jul 2015

Keywords

Antigens, CD
Antigens, Differentiation, Myelomonocytic
Carotid Stenosis
Copper Radioisotopes
Endarterectomy, Carotid
Gene Expression
Humans
Macrophages
Magnetic Resonance Imaging
Octreotide
Organometallic Compounds
Positron-Emission Tomography
Receptors, Cell Surface

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Pedersen, S. F., Sandholt, B. V., Keller, S. H., Hansen, A. E., Clemmensen, A. E., Sillesen, H., Højgaard, L., Ripa, R. S., & Kjær, A. (2015). ⁶⁴Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques: studies in patients undergoing endarterectomy. Arteriosclerosis, Thrombosis, and Vascular Biology, 35(7), 1696-1703. https://doi.org/10.1161/ATVBAHA.114.305067

⁶⁴Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques: studies in patients undergoing endarterectomy. / Pedersen, Sune Folke; Sandholt, Benjamin Vikjær; Keller, Sune Høgild et al.
In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 35, No. 7, 27.07.2015, p. 1696-1703.

Research output: Contribution to journal › Journal article › Research › peer-review

Pedersen, SF, Sandholt, BV, Keller, SH, Hansen, AE , Clemmensen, AE , Sillesen, H , Højgaard, L , Ripa, RS & Kjær, A 2015, '⁶⁴Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques: studies in patients undergoing endarterectomy', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 35, no. 7, pp. 1696-1703. https://doi.org/10.1161/ATVBAHA.114.305067

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title = "64Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques: studies in patients undergoing endarterectomy",

abstract = "Objective-A feature of vulnerable atherosclerotic plaques of the carotid artery is high activity and abundance of lesion macrophages. There is consensus that this is of importance for plaque vulnerability, which may lead to clinical events, such as stroke and transient ischemic attack. We used positron emission tomography (PET) and the novel PET ligand [64Cu] [1,4,7,10-tetraazacyclododecane-N,N′,N″,N⌄-tetraacetic acid]-d-Phe1,Tyr3-octreotate (64Cu-DOTATATE) to specifically target macrophages via the somatostatin receptor subtype-2 in vivo. Approach and Results-Ten patients underwent simultaneous PET/MRI to measure 64Cu-DOTATATE uptake in carotid artery plaques before carotid endarterectomy. 64Cu-DOTATATE uptake was significantly higher in symptomatic plaque versus the contralateral carotid artery (P<0.001). Subsequently, a total of 62 plaque segments were assessed for gene expression of selected markers of plaque vulnerability using real-time quantitative polymerase chain reaction. These results were compared with in vivo 64Cu-DOTATATE uptake calculated as the mean standardized uptake value. Univariate analysis of real-time quantitative polymerase chain reaction and PET showed that cluster of differentiation 163 (CD163) and CD68 gene expression correlated significantly but weakly with mean standardized uptake value in scans performed 85 minutes post injection (P<0.001 and P=0.015, respectively). Subsequent multivariate analysis showed that CD163 correlated independently with 64Cu-DOTATATE uptake (P=0.031) whereas CD68 did not contribute significantly to the final model. Conclusions-The novel PET tracer 64Cu-DOTATATE accumulates in atherosclerotic plaques of the carotid artery. CD163 gene expression correlated independently with 64Cu-DOTATATE uptake measured by real-time quantitative polymerase chain reaction in the final multivariate model, indicating that 64Cu-DOTATATE PET is detecting alternatively activated macrophages. This association could potentially improve noninvasive identification and characterization of vulnerable plaques.",

keywords = "Antigens, CD, Antigens, Differentiation, Myelomonocytic, Carotid Stenosis, Copper Radioisotopes, Endarterectomy, Carotid, Gene Expression, Humans, Macrophages, Magnetic Resonance Imaging, Octreotide, Organometallic Compounds, Positron-Emission Tomography, Receptors, Cell Surface",

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year = "2015",

month = jul,

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doi = "10.1161/ATVBAHA.114.305067",

language = "English",

volume = "35",

pages = "1696--1703",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

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TY - JOUR

T1 - 64Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques

T2 - studies in patients undergoing endarterectomy

AU - Pedersen, Sune Folke

AU - Sandholt, Benjamin Vikjær

AU - Keller, Sune Høgild

AU - Hansen, Adam Espe

AU - Clemmensen, Andreas Ettrup

AU - Sillesen, Henrik

AU - Højgaard, Liselotte

AU - Ripa, Rasmus Sejersten

AU - Kjær, Andreas

PY - 2015/7/27

Y1 - 2015/7/27

N2 - Objective-A feature of vulnerable atherosclerotic plaques of the carotid artery is high activity and abundance of lesion macrophages. There is consensus that this is of importance for plaque vulnerability, which may lead to clinical events, such as stroke and transient ischemic attack. We used positron emission tomography (PET) and the novel PET ligand [64Cu] [1,4,7,10-tetraazacyclododecane-N,N′,N″,N⌄-tetraacetic acid]-d-Phe1,Tyr3-octreotate (64Cu-DOTATATE) to specifically target macrophages via the somatostatin receptor subtype-2 in vivo. Approach and Results-Ten patients underwent simultaneous PET/MRI to measure 64Cu-DOTATATE uptake in carotid artery plaques before carotid endarterectomy. 64Cu-DOTATATE uptake was significantly higher in symptomatic plaque versus the contralateral carotid artery (P<0.001). Subsequently, a total of 62 plaque segments were assessed for gene expression of selected markers of plaque vulnerability using real-time quantitative polymerase chain reaction. These results were compared with in vivo 64Cu-DOTATATE uptake calculated as the mean standardized uptake value. Univariate analysis of real-time quantitative polymerase chain reaction and PET showed that cluster of differentiation 163 (CD163) and CD68 gene expression correlated significantly but weakly with mean standardized uptake value in scans performed 85 minutes post injection (P<0.001 and P=0.015, respectively). Subsequent multivariate analysis showed that CD163 correlated independently with 64Cu-DOTATATE uptake (P=0.031) whereas CD68 did not contribute significantly to the final model. Conclusions-The novel PET tracer 64Cu-DOTATATE accumulates in atherosclerotic plaques of the carotid artery. CD163 gene expression correlated independently with 64Cu-DOTATATE uptake measured by real-time quantitative polymerase chain reaction in the final multivariate model, indicating that 64Cu-DOTATATE PET is detecting alternatively activated macrophages. This association could potentially improve noninvasive identification and characterization of vulnerable plaques.

AB - Objective-A feature of vulnerable atherosclerotic plaques of the carotid artery is high activity and abundance of lesion macrophages. There is consensus that this is of importance for plaque vulnerability, which may lead to clinical events, such as stroke and transient ischemic attack. We used positron emission tomography (PET) and the novel PET ligand [64Cu] [1,4,7,10-tetraazacyclododecane-N,N′,N″,N⌄-tetraacetic acid]-d-Phe1,Tyr3-octreotate (64Cu-DOTATATE) to specifically target macrophages via the somatostatin receptor subtype-2 in vivo. Approach and Results-Ten patients underwent simultaneous PET/MRI to measure 64Cu-DOTATATE uptake in carotid artery plaques before carotid endarterectomy. 64Cu-DOTATATE uptake was significantly higher in symptomatic plaque versus the contralateral carotid artery (P<0.001). Subsequently, a total of 62 plaque segments were assessed for gene expression of selected markers of plaque vulnerability using real-time quantitative polymerase chain reaction. These results were compared with in vivo 64Cu-DOTATATE uptake calculated as the mean standardized uptake value. Univariate analysis of real-time quantitative polymerase chain reaction and PET showed that cluster of differentiation 163 (CD163) and CD68 gene expression correlated significantly but weakly with mean standardized uptake value in scans performed 85 minutes post injection (P<0.001 and P=0.015, respectively). Subsequent multivariate analysis showed that CD163 correlated independently with 64Cu-DOTATATE uptake (P=0.031) whereas CD68 did not contribute significantly to the final model. Conclusions-The novel PET tracer 64Cu-DOTATATE accumulates in atherosclerotic plaques of the carotid artery. CD163 gene expression correlated independently with 64Cu-DOTATATE uptake measured by real-time quantitative polymerase chain reaction in the final multivariate model, indicating that 64Cu-DOTATATE PET is detecting alternatively activated macrophages. This association could potentially improve noninvasive identification and characterization of vulnerable plaques.

KW - Antigens, CD

KW - Antigens, Differentiation, Myelomonocytic

KW - Carotid Stenosis

KW - Copper Radioisotopes

KW - Endarterectomy, Carotid

KW - Gene Expression

KW - Humans

KW - Macrophages

KW - Magnetic Resonance Imaging

KW - Octreotide

KW - Organometallic Compounds

KW - Positron-Emission Tomography

KW - Receptors, Cell Surface

U2 - 10.1161/ATVBAHA.114.305067

DO - 10.1161/ATVBAHA.114.305067

M3 - Journal article

C2 - 25977567

SN - 1079-5642

VL - 35

SP - 1696

EP - 1703

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

IS - 7

ER -